The renin-angiotensin system is very important in the physiologic control of blood pressure and fluid balance. That said, it is also important to realize that the physiologic actions of the renin-angiotensin system are more complex than simple blood pressure control, as evidenced by the phenotype of knockout mice that lack a functional renin-angiotensin system. Our group has created mice that lack ACE. These animals have very low systolic blood pressures and are unable to effectively concentrate urine. However, what was most dramatic and unexpected was that the mice have a marked under-development of the renal medulla. We hypothesize that part of the pathophysiology of the renal phenotype is due to the lack of the local generation of angiotensin II within the kidney. This application proposes experiments to study the renal phenotype in ACE knockout mice. Our approach will be to create new strains of genetically-altered mice expressing ACE activity in selected portions of the renal nephron. These studies are designed to discriminate between angiotensin II as a local factor necessary for renal development and function, and other pathophysiologic mechanisms that may be responsible for the renal phenotype of these animals. We also describe a second line of ACE knockout mice that lacks the tissue bound form of this enzyme. The phenotype of these animals suggests that it is expression of ACE within tissues, as opposed to plasma ACE activity, that is responsible for regulating blood pressure. Using homologous recombination to create novel strains of genetically altered mice, we will examine precisely which tissues are most responsible for blood pressure control.